BioMarin Resubmits BLA for Hemophilia A Gene Therapy Val-Rox


A prior resubmission in June 2022 was delayed with requests for additional durability and safety data.

BioMarin has resubmitted the biologics license application (BLA) to the FDA for valoctocogene roxaparvovec (val-rox; BMN-270), an adeno-associated virus (AAV)-based gene therapy intended to treat hemophilia A.1

BioMarin originally submitted a BLA for val-rox in August 2020, which was rejected with a request for 2-year follow-up data.2 A prior resubmission in June 2022 was delayed with requests for additional durability and safety data.3 Meanwhile, val-rox was approved for hemophilia A in the EU in August 2022 with conditional marketing authorization.4

BioMarin’s new FDA BLA resubmission includes data from the 2-year results of the GENEr8-1 phase 3 study (NCT03370913) and additional 5-year follow-up data from an on-going phase 1/2 dose-escalation study.1 Patients treated with val-rox in the global GENEr8-1 clinical trial showed stable and durable control of bleeding and reductions in both mean annualized bleeding rate and mean annualized Factor VIII infusion rate.

A draft report released by the Institute for Clinical and Economic Review (ICER) in mid-September 2022 evaluated data from the GENEr8-1 study and compared val-rox favorably with standards of care for hemophilia A in terms of patient benefit and cost, though the support came with several caveats and substantial uncertainty.5 Around the same time, BioMarin also revealed in an SEC filing that it is investigating a case of B-cell acute lymphoblastic leukemia in a patient who received val-rox.6

"We are pleased to reach this point in the development program for val-rox and look forward to working with the FDA with the goal of bringing a potentially transformative therapy to people with severe hemophilia A in the United States," Hank Fuchs, MD, president of worldwide research and development, BioMarin, said in a statement.1 "This large and robust data set provided in this BLA resubmission shows an encouraging efficacy profile. We remain committed to sharing these data with the public, along with even longer-term data generated through our ongoing clinical trials and any post-approval studies, to further our understanding of AAV gene therapy in severe hemophilia A and of gene therapies more broadly."

Thus far, 6x1013 vg/kg doses of val-rox have been generally well-tolerated without delayed-onset treatment related adverse events (AEs). Common AEs associated with val-rox include transient infusion associated reactions, mild to moderate rises in liver enzymes without long-lasting clinical sequelae, and alanine aminotransferase elevation, with the latter being noted as most common. Aspartate aminotransferase elevation has been observed in 63% of clinical trial participants, while nausea and headache have been observed in 34% of participants, and fatigue has been observed in 28% of participants. To date, no participants have developed inhibitors to Factor VIII, and thromboembolic events or malignancy associated with val-rox have not been reported.

In addition to the previously mentioned studies, val-rox is also being investigated in a phase 3 clinical trial (Study 270-303) at a dose of 6x1013 vg/kg in combination with prophylactic corticosteroids for patients with severe hemophilia A. Another phase 1/2 study of the gene therapy at 6x1013 vg/kg for patients with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) is also underway, as is a phase 1/2 study at the same dose for patients with severe hemophilia A with active or prior Factor VIII inhibitors (Study 270-205). 

BioMarin is not the only company currently investigating gene therapy for the treatment of hemophilia. The ICER report also covered CSL’s etranacogenedezaparvovec (EtranaDez), an investigational gene therapy intended for the treatment of hemophilia B.5 This September, Pfizer and Sangamo also announced reopening of enrollment in the phase 3 AFFINE study (NCT04370054) of giroctocogene fitelparvovec, an investigational gene therapy intended to treat moderately severe to severe hemophilia A.7 Meanwhile, the New England Journal of Medicine reported promising data from a clinical trial of hemophilia B gene therapy FLT180a (verbrinacogene setparvovec; Freeline Therapeutics) in July 2022.8

1. Biomarin resubmits biologics license application (BLA) for valoctocogeneroxaparvovec AAV gene therapy for severe hemophilia A to the FDA. News release. BioMarin Pharmaceutical Inc. September 29, 2022. 
2. BioMarin delays hemophilia a therapy valoctocogene roxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022.
3. BioMarin delays hemophilia a therapy valoctocogeneroxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022.
4. First gene therapy for adults with severe hemophilia A, BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec), approved by European Commission (EC). News release. BioMarin. August 24, 2022.,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC
5. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: effectiveness and value. Draft Evidence Report. The Institute for Clinical and Economic Review. September 13, 2022.
6. Securities and Exchange Commission, Form 8-K. BioMarin Pharmaceuticals. September 12, 2022. Accessed September 14, 2022.
7. Pfizer and Sangamo Therapeutics announce phase 3 trial of investigational gene therapy for hemophilia A has re-opened recruitment. News release. Pfizer. September 23, 2022.
8. Chowdary P, Shapiro S, Makris M, et al. Phase 1–2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022; 387:237-247 doi: 10.1056/NEJMoa2119913

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